Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Gedeon Richter Plc., Gyömrői út 19-21., 1103 Budapest, Hungary
Pharmacotherapeutic group: Intrauterine contraceptives, plastic IUD with progestogen
ATC code: G02BA03
Levonorgestrel is a progestogen used in gynaecology in various ways: as the progestogen component in oral contraceptives, in hormonal replacement therapy or alone for contraception in minipills and subdermal implants. Levonorgestrel can also be administered directly into the uterine cavity as an IUS. This allows a very low daily dosage, as the hormone is released directly into the target organ.
The contraceptive mechanism of action of the levonorgestrel IUS is based mainly on hormonal effects producing the following changes:
The physical presence of the system in the uterus would also be expected to make a minor contribution to its contraceptive effect.
When inserted according to the insertion instructions, Levosert offers contraceptive protection. Contraceptive efficacy of Levosert was investigated in a large clinical trial. The cumulative pregnancy rate calculated as the Pearl Index (PI) in women aged 16 to 35 years, inclusive, was 0.15 (95% CI: 0.02, 0.55) at the end of year 1 and 0.18 (95% CI: 0.08, 0.33) at the end of year 6.
19% of Levosert users became amenorrhoeic by the end of the first year of use, 27% by the end of the second year of use, 37% by the end of the third year of use, 37% by the end of the fourth year of use, and 40% by the end of the fifth year of use and 40% by the end of the sixth year of use.
In idiopathic menorrhagia, prevention of proliferation of the endometrium is the probable mechanism of action of levonorgestrel IUS in reducing blood loss.
In the clinical trial evaluating women with heavy menstrual bleeding (≥ 80 mL per menstrual cycle), Levosert achieved a significant reduction in menstrual blood loss within 3 to 6 months of treatment. The volume of menstrual bleeding was decreased by 88% in women with heavy menstrual bleeding by the end of three months of use and 82% reduction was sustained for the duration of the study (12 months). Heavy menstrual bleeding caused by submucosal fibroids may respond less favourably. Reduced bleeding promotes an increase of blood haemoglobin in patients with heavy menstrual bleeding.
The initial in vivo release rate of 20.1 micrograms/day levonorgestrel from Levosert decreases to 17.5 micrograms/day during the first year and 8.6 micrograms /day during the sixth year. Levonorgestrel is delivered directly into the uterine cavity with low plasma concentrations (252 ± 123 pg/mL 7 days after insertion and 93 ± 45 pg/mL after 6 years) resulting in only minor systemic effects.
The pharmacokinetics of levonorgestrel itself have been extensively investigated and reported in the literature. A half life of 20 hours is considered the best estimate although some studies have reported values as short as 9 hours and others as long as 80 hours. Another important finding, although one in agreement with experience with other synthetic steroids, has been marked differences in metabolic clearance rates among individuals, even when administration was by the intravenous route. Levonorgestrel is extensively bound to proteins (mainly sex hormone binding globulin [SHBG]) and extensively metabolised to a large number of inactive metabolites.
Non-clinical data reveal no special hazard for humans other than the information already included in other sections of the SmPC. These data are based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
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